Allergic diseases such as anaphylaxis, allergic rhinitis, asthma, atopic dermatitis, food allergies and urticaria, inflict up to 20% of the population in many countries and are increasing in prevalence (Wuthrich B., Int. Arch. Allergy Appl. Immunol., 90, pp 3-10, 1989).
Allergic diseases are mediated by immunoglobulin E (IgE), while the type-2 T helper (Th2) cell, mast cell and eosinophil are proven to play important roles in that process (Maggi E., Immunotechnology, 3, pp 233-244, 1998; Pawankar R., Curr. Opin. Allergy Clin. Immunol., 1, pp 3-6, 2001; Vercelli D., Clin. Allergy Immunol., 16, pp 179-196, 2002).
Without helminth infection or other stimuli, IgE is normally one of abundant immunoglobulin isotypes found in human serum as well as several species of experimental animals (Maggi E., Immunotechnology, 3, pp 233-244, 1998; Coffman R L and Carty J., J. Immunotechnology, 136, pp 949-954, 1986). According to the “Th2 hypothesis”, IgE production is favored in the immunological condition in which humoral immunity mediated by Th2 cells and related cytokines such as IL-4, IL-5 and IL-13, is predominant (Maggi E., Immunotechnology, 3, pp 233-244, 1998). The current view of the progress of allergic diseases is that genetic and environmental factors interact with each other, leading to the production of IL-4 through the Stat6-mediated signaling pathway and the activation of specific transcription factors such as c-Maf, GATA3, NIP45 and NFATc in native T cells, and eventually resulting in the development of allergen-specific T helper 2 CD4+ cells. Once generated, allergen-activated Th2 cells secrete IL-4, IL-5 and IL-13. IL-4 and IL-5 induce the production of IgE and IgG1 by B cells as well as the stimulation of the development of eosinophils in bone marrow and their recruitment into inflamed tissues (Erb K. J.; Immunol. Today, 20, pp 317-322, 1999; Rothenberg M E., N. Engl. J. Med., 338, pp 1592-1600, 1998). IL-13 is a cytokine closely related to IL-4 and binds to the IL-4 receptor alpha chain inducing allergic phenotypes independently of IL-4, IgE or eosinophils (Wills-Karp M., et al., Science, 282, pp 2258-2261, 1998; Grunig G., et al., Science, 282, pp 2261-2263, 1998).
Circulating IgE binds to two isoforms of IgE receptors: high-affinity IgE receptors (FcεRI) present on the surface of mast cells and basophils, and low affinity IgE receptors (FcεRII or CD23) present on the surfaces of lymphocytes, eosinophils, platelets and macrophages. It is believed that the most important factor governing the pathogenesis of allergic disorders is the cross-linkage of IgE receptors on mast cells, after encountering allergen and the consequent degranulation of mast cells. The molecules released by mast cells include histamine, heparin, proteases and free radicals, which mediate a variety of biological effects including vasodilation, intestinal and/or bronchial smooth muscle contraction, mucous secretion and local proteolysis. Following initial immediate reaction of the mast cells, an influx of eosinophils, basophils and lymphocytes occurs 6-24 hours later. This late-phase response can lead to chronic tissue inflammation continuously exposed to antigens.
Conventional drugs for the treatment of allergic disorders include anti-histamines, steroidal or non-steroidal anti-inflammatory drugs and leukotriene antagonists. These drugs are useful mainly for symptomatic effects, and fail to provide with such treatments that the fundamental cure of allergic diseases such as alleviating excessive humoral immunity or suppressing IgE production is required. The hypothesis that reducing serum IgE level could improve allergic symptoms was demonstrated by clinical trials of the chimeric anti-IgE antibody (CGP-51901) and recombinant humanized monoclonal antibody (rhuMAB-E25) (Fahy J V et al., Am. J. Respir. Crit. Care. Med., 155, pp 1828-1834, 1997). Diacyl benzimidazole analogs and bacterial polysaccharides that inhibit IgE synthesis and secretion have been described in U.S. Pat. No. 6,369,091 and U.S. patent application Ser. No. 20020041885, respectively.
The only method for fundamental treatment of allergy is carrying out immunotherapy or desensitization therapy. The immunotherapy is treatment method, which reduces hypersensitivity to allergic origin and improves allergic symptom by administering refined allergen for long period to allergic patient with gradually increasing their dosage. After their introduction in 1911, the immunotherapy has been used for treatment of allergic disease such as allergic rhinitis, allergic asthma, bee poisoning and so on by using antigen-specific IgE antibody. Major mechanism reducing hypersensitivity has not been clearly found yet, but it is known that increase of IgG concentration while reducing IgE concentration induces normal immunity reaction.
Actinidia arguta, A. polygama, and A. kolomikta belonged to Actinidiaceae, are distributed in Siberia, the northern area of China, North and South Korea. More than 30 species belonged to Actinidiaceae has been reported. Among those, the fruit of A. chinensis or A. delicious have been named as kiwi and Actinidia arguta and other same genus fruit have been used as materials of Chinese medicine named as ‘mihudo’ to treat liver disease, gastrointestinal disease and urogenital lithiasis without toxicity (Seoul National University Natural Products Science, Tradi-Medi Data Base, dongbang media Co. Ltd. 1999). However, there have been no report or suggestion about the treatment and prevention of allergic disease and non-allergic inflammatory disease using by Actinidia fruit.
Meanwhile, there has been concentrated effort to investigate effective anti-allergy and anti-inflammatory natural products.
Korea Patent Application No. 92-11752 disclosed an anti-inflammatory, anti-allergic and anti-rheumatic drug comprising biflavonoid such as 4′-O-methyl ochnaflavone isolated from Lonicera japonica, which shows various allergy or inflammation treating activity. Korea Patent Registration No. 100744 disclosed anti-inflammatory, anti-allergic and anti-rheumatic drug comprising several biflavonoid compounds isolated from the leaves of Ginko biloba. Several Oriental medicine recipes comprising Siegesbeckia glabrescens have been reported to have IgE-reducing activity (Kim H. M et al., Phytother. Res., 15, pp 572-576, 2001). Furthermore, lots of medicinal herbs have been found to be rich sources of histamine release inhibitors or anti-inflammatory drugs.
However, there has been not reported or disclosed about anti-allergic and anti-inflammatory action of hardy kiwifruit extract in any of above literatures.
To investigate an anti-allergic and anti-inflammatory drugs among Chinese herbs, the inventors of the present invention have intensively carried out in vivo and in vitro experiments concerning the effects of hardy kiwifruit extract on the change of Th1/Th2 cytokines and IgE, IgG subtype in human serum as well as inhibition test of histamine release from mice peritoneal mast cells and rat paw edema test.